Coated medical device

ABSTRACT

A coated medical device ( 10 ) including a structure ( 12 ) adapted for introduction into a passage or vessel of a patient. The structure is formed of preferably a non-porous base material ( 14 ) having a bioactive material layer ( 18 ) disposed thereon. The medical device is preferably an implantable stent or balloon ( 26 ) of which the bioactive material layer is deposited thereon. The stent can be positioned around the balloon and another layer of the bioactive material posited over the entire structure and extending beyond the ends of the positioned stent. The ends of the balloon extend beyond the ends of the stent and include the bioactive material thereon for delivering the bioactive material to the cells of a vessel wall coming in contact therewith. The balloon further includes a layer of hydrophilic material ( 58 ) positioned between the base and bioactive material layers of the balloon.

TECHNICAL FIELD

This invention relates generally to human and veterinary medical devicesand, more particularly, to coated medical devices incorporating drugs,bioactive agents, therapeutic agents or diagnostic agents.

BACKGROUND OF THE INVENTION

It has become common to treat a variety of medical conditions bytemporarily or permanently introducing a coated medical device, and, inparticular, a coated medical implanted device partly or completely intothe esophagus, trachea, colon, biliary tract, urinary tract, vascularsystem or other location within a human or veterinary patient. Manytreatments of the vascular or other systems entail the introduction of adevice such as a stent, a catheter, a balloon, a wire guide, a cannulaor the like. For this purpose, a stent may most simply be considered asa cylinder of relatively short length which opens a body passage orlumen or which maintains a body passage or lumen in an open condition.In addition, balloons such as angioplasty or dilation balloons areexpanded to open a body passage or vessel lumen, thereby causingpotential trauma or injury to the expanded passage or vessel.

Such medical devices are generally capable of serving their intendedpurposes quite well. Some drawbacks can be encountered during their use,however. For example, when a device is introduced into and manipulatedthrough the vascular system of a patient, the blood vessel walls can bedisturbed or injured. Clot formation or thrombosis often results at theinjured site, causing stenosis (closure) of the blood vessel. Moreover,if the medical device is left within the patient for an extended periodof time, thrombus often forms on the device itself, again causingstenosis. As a result, the patient is placed at risk of a variety ofcomplications, including heart attack, pulmonary embolism, and stroke.Thus, the use of such a medical device can entail the risk of preciselythe problems that its use was intended to ameliorate.

When medical devices such as stents and, in particular, coated stentsare implanted in a vessel lumen, edge effect trauma occurs to the tissueat and beyond the ends of the implanted stent. This trauma or injury canbe the result of the implanted stent causing injury to the vessel wall.However, delivery of such an implanted stent normally includes the useof an inflatable balloon of which the stent is mounted thereon with theends of the balloon extending axially beyond the ends of the stent. Whenthe balloon is inflated to deliver the stent, the ends of the balloonextending beyond that of the stent inflate so as to dilate and injurethe tissue extending beyond the ends of the stent. Should the stent becoated or include a therapeutic agent, the therapeutic or treatmentagent can possibly cause injury to the tissue extending beyond the endsof the stent. This treatment could include a chemical, radiation, orbiochemical agent or treatment. Furthermore, delivery agents such aspolymers and the like used to deliver the treatment agent can also causethis edge effect reaction to the tissue extending beyond the ends of theimplanted stent. However, it is to be understood that regardless of thecause of the trauma or injury to the vessel wall, the tissue will reactsuch as with smooth muscle cell proliferation and the like therebycreating an adverse reaction and subsequent closure or stenosis of thevessel.

Another way in which blood vessels undergo stenosis is through disease.Probably the most common disease causing stenosis of blood vessels isatherosclerosis. Many medical devices and therapeutic methods are knownfor the treatment of atherosclerotic disease. One particularly usefultherapy for certain atherosclerotic lesions is percutaneous transluminalangioplasty (PTA). During PTA, a balloon-tipped catheter is inserted ina patient's artery, the balloon being deflated. The tip of the catheteris advanced to the site of the atherosclerotic plaque to be dilated. Theballoon is placed within or across the stenotic segment of the artery,and then inflated. Inflation of the balloon “cracks” the atheroscleroticplaque and expands the vessel, thereby relieving the stenosis, at leastin part.

While PTA presently enjoys wide use, it suffers from two major problems.First, the blood vessel may suffer acute occlusion immediately after orwithin the initial hours after the dilation procedure. Such occlusion isreferred to as “abrupt closure.” Abrupt closure occurs in perhaps fivepercent or so of the cases in which PTA is employed, and can result inmyocardial infarction and death if blood flow is not restored promptly.The primary mechanisms of abrupt closures are believed to be elasticrecoil, arterial dissection and/or thrombosis. It has been postulatedthat the delivery of an appropriate agent (such as an antithrombic)directly into the arterial wall at the time of angioplasty could reducethe incidence of thrombotic acute closure, but the results of attemptsto do so have been mixed.

A second major problem encountered in PTA is the re-narrowing of anartery after an initially successful angioplasty. This re-narrowing isreferred to as “restenosis” and typically occurs within the first sixmonths after angioplasty. Restenosis is believed to arise through theproliferation and migration of cellular components from the arterialwall, as well as through geometric changes in the arterial wall referredto as “remodeling.” It has similarly been postulated that the deliveryof appropriate agents directly into the arterial wall could interruptthe cellular and/or remodeling events leading to restenosis. However,like the attempts to prevent thrombotic acute closure, the results ofattempts to prevent restenosis in this manner have been mixed.

Non-atherosclerotic vascular stenosis may also be treated by PTA. Forexample, Takayasu arteritis or neurofibromatosis may cause stenosis byfibrotic thickening of the arterial wall. Restenosis of these lesionsoccurs at a high rate following angioplasty, however, due to thefibrotic nature of the diseases. Medical therapies to treat or obviatethem have been similarly disappointing.

A device such as an intravascular stent can be a useful adjunct to PTA,particularly in the case of either acute or threatened closure afterangioplasty. The stent is placed in the dilated segment of the artery tomechanically prevent abrupt closure and restenosis. Unfortunately, evenwhen the implantation of the stent is accompanied by aggressive andprecise antiplatelet and anticoagulation therapy (typically by systemicadministration), the incidence of thrombotic vessel closure or otherthrombotic complication remains significant, and the prevention ofrestenosis is not as successful as desired. Furthermore, an undesirableside effect of the systemic antiplatelet and anticoagulation therapy isan increased incidence of bleeding complications, most often at thepercutaneous entry site.

Other conditions and diseases are treatable with stents, catheters,cannulae and other medical devices inserted into the esophagus, trachea,colon, biliary tract, urinary tract and other locations in the body. Awide variety of bioactive materials (drugs, therapeutic agents,diagnostic agents and other materials having biological orpharmacological activity within a patient) have been applied to suchmedical devices for the purpose of introducing such materials into thepatient. Unfortunately, the durable application of bioactive materialsto stents and the like, sufficient for such introduction to successfullyoccur, is often problematic. A range of containment or layeringmaterials have been applied to such devices to permit the timed releaseof bioactive materials from such devices, or even to permit bioactivematerials to be applied to such devices at all. Unfortunately, the useof such containment materials can significantly increase the time andcost of manufacturing suitable implantable devices. Moreover, somebioactive materials may not be able to withstand incorporation in knowncontainment materials. Additionally, certain containment materials maynot be biocompatible and may cause problems of the type desired to bereduced.

It would be desirable to develop devices and methods for reliablydelivering suitable therapeutic and diagnostic agents, drugs and otherbioactive materials directly into a body portion during or following amedical procedure, so as to treat or prevent the conditions and diseasesmentioned above, for example, to prevent abrupt closure and/orrestenosis of a body portion such as a passage, lumen or blood vessel.It would also be desirable to limit systemic exposure of the patient tosuch bioactive materials. This would be particularly advantageous intherapies involving the delivery of a chemotherapeutic agent to aparticular organ or site through an intravenous catheter (which itselfhas the advantage of reducing the amount of agent needed for successfultreatment), by preventing stenosis both along the catheter and at thecatheter tip. It would be desirable to similarly improve othertherapies. Of course, it would also be desirable to avoid degradation ofthe agent, drug or bioactive material during its incorporation on orinto any such device. It would further be highly desirable to develop amethod for coating an implantable medical device with a drug,therapeutic agent, diagnostic agent or other bioactive material whichentailed a minimum number of steps, thereby reducing the ultimate costof treating the patient. It would be desirable to deliver the bioactivematerial without causing additional problems with a poor biocompatiblecarrier or containment material. Finally, it would be highly desirableto develop a method for coating an implantable medical device with adrug, therapeutic agent, diagnostic agent or other bioactive materialwhich could be carried out in such a way as to minimize anyenvironmental or personal risks or inconveniences associated with themanufacture of the device.

In addition, it is desirable to develop devices and methods fordelivering a suitable therapeutic and diagnostic agent, drugs and otherbioactive materials to those areas of the passage or vessel just beyond,for example, the ends of an implanted coated stent to treat, minimize orpreferably eliminate “edge effects” that ultimately cause trauma to thevessel wall and subsequent occlusion or stenosis of the vessel.Similarly, it would be desirable to provide such a medical device fortreating passage or vessel tissue that has been affected by a previouslyimplanted device.

SUMMARY OF THE INVENTION

The foregoing problems are solved and a technical advance is achieved inan illustrative embodiment of a coated medical device of the presentinvention in which a drug, therapeutic agent, diagnostic agent or otherbioactive or pharmacologically active material is delivered or applieddirectly to the surface of the passage or vessel wall. In oneillustrative embodiment, the coated medical device comprises anexpandable balloon of which a bioactive material is applied thereto andcoats the outer surface of the expandable balloon. In a preferredillustrative embodiment, the bioactive material is a lipophilic materialsuch as paclitaxel or dexamethazone which is an anti-inflammatorysteroid for attachment to the cell wall. This lipophilic bioactivematerial is attracted by the cell membrane of the endothelial cells ofthe inner wall and initially adheres to these cells when put in contacttherewith. The lipophilic material is then drawn or transferred into thecell membrane. In addition, when the endothelial cells are injured orremoved from the inner wall, smooth muscle cells are then exposed whichalso include lipids and attract the lipophilic bioactive material. Thedelivery and/or attachment of this lipophilic bioactive material ispreferably accomplished by bringing the lipophilic bioactive material inphysical or direct contact with the endothelial or smooth muscle cells.Thus, the medical device of the present invention not only includespreferably an expandable balloon but an expandable balloon with acoating of the preferred lipophilic bioactive material. When the balloonis expanded at the treatment site, the coating material and, inparticular, the lipophilic bioactive material is brought into direct orphysical contact with the inner wall cells of the vessel and thustransferred from the balloon to the desired passage or vessel wallcells. When transferring the preferred lipophilic bioactive material tothe vessel wall, preferred inflation times of up to and about one minuteare used in delivering the lipophilic bioactive material. To furtherimprove the treatment of the vessel wall and transfer the bioactivematerial thereto, a hydrophilic material is applied to the base materialof the device of which the preferred lipophilic bioactive material isapplied or coated thereon. This hydrophilic material, also known as aslip coating lessens the adhesion of the base material to the lipophilicbioactive material and helps facilitate a delivery of the lipophilicmaterial to the vessel cells at the delivery site. In addition, bloodfor example, helps wet the slip coating and further enhance the deliveryprocess and deliver as much of the lipophilic bioactive material to thevessel wall. Thus, by selecting the ratio of lipophilic to hydrophiliccoating materials, the delivery of the lipophilic material to the vesselwalls can be better controlled. This ratio can be altered depending onthe particular type of base material of the delivery device and theparticular bioactive material being delivered to the vessel wall.

The medical device of the present invention such as a balloon is coatedwith the preferred lipophilic bioactive material with the balloon in anexpanded or inflated condition. Thus, a larger and more complete dose ofthe lipophilic material can be applied to the outer surface of theballoon. The balloon is then deflated or evacuated so that the balloonwall material can be folded and assume its smallest outer diameter forinsertion into the vessel or for placement of another device such as acoated stent over the folded outer surface of the balloon. The medicaldevice such as the stent may also be coated with a bioactive substancefor minimizing any undesirable response to the traumatized or stenoticvessel wall. In another preferred embodiment of the present invention,another layer of bioactive material such as a lipophilic bioactivematerial is applied and/or coated over the folded balloon and medicaldevice such as a stent mounted on the balloon. Advantageously, thisincreases the amount of bioactive material that can be delivered to thevessel wall to treat and minimize adverse reactions due to treatment ofthe vessel tissue. When the balloon and stent are delivered to thetreatment site, the balloon is inflated to expand and deliver the stentto the treatment site. Thus, the bioactive material is brought in directcontact with the vessel wall not only with the stent but with theballoon coming in contact with the vessel wall extending beyond the endsof the stent. Thus, the preferred lipophilic bioactive material isapplied to the vessel wall extending beyond the ends of the implantedstent and thus minimizing, if not eliminating, the undesirable edgeeffect or restenosis that is often observed with the implantation ofstents not utilizing material on the balloon for the delivery process.Advantageously, the application or coating of the balloon material in aninflated condition allows for a full application of the bioactivematerial between the folds of the balloon and thus full circumferentialdelivery of the lipophilic bioactive material to the inner surface ofthe vessel. The foregoing problems are solved and a technical advance isachieved in an illustrative embodiment of a medical device of thepresent invention coated (at least in part) with a drug, therapeuticagent, diagnostic agent or other bioactive or pharmacologically activematerial. (Hereinafter, any or all of these will be collectivelyreferred to as “a bioactive material” or “bioactive materials.”). Thespecific improvement of the present invention entails attaining adesired surface roughness, or texturing, on the surface of the device bywhatever treatment of the surface and applying the bioactive materialdirectly to that roughened or textured surface without the need of anyfurther overlying or containment layer or coating. Unexpectedly, thisstraightforward expedient yields a coated implantable medical devicewhich is sufficiently durable to withstand the desired implantationwithout suffering an unacceptable amount of loss (if any) of bioactivematerial from the device. In one aspect of the invention, at least apart of the surface of the device, for example the outer surface of astent, is treated to produce a roughened, uneven, or unsmooth surface,and the bioactive material is formed or posited on at least the part ofthe surface. The degree of surface treatment is controlled to providesufficient adhesion of the bioactive material to the device surface.

In the preferred embodiment of the medical device of the presentinvention, the device first comprises a structure adapted for temporaryor permanent introduction into the esophagus, trachea, colon, biliarytract, urinary tract, vascular system or other location in a human orveterinary patient. The structure comprises a base material (preferablynon-porous) having a roughened or textured surface. The surface of thebase material can be roughened or textured by etching but is preferablyroughened or textured by abrasion with an abrasive grit, most preferablysodium bicarbonate (USP).

The medical device of the present invention also comprises a layer ofbioactive material posited directly upon the roughened or texturedsurface of the base material of the structure. Furthermore, the deviceadvantageously does not require or is free of any additional coating orlayer atop the layer of bioactive material.

As described in more detail below, the base material of the structureand the bioactive material posited on that base material can compriseany of a wide range of suitable materials. The selection of a specificcombination of base material, bioactive material and surface roughnessor texture depends upon the intended use of the medical device. Althoughtexture may have a meaning of a repeatable pattern, this is clearly notthe intent. The surface of the stent is that of any topography, whetherrepeatable or not, that helps improve adhesion of the bioactive materialon the base material or modification thereof. Hereinafter, a texturedsurface will include a roughened, uneven, or unsmooth surface. Thesuitability of a chosen combination can readily be determined by anadhesion test which simulates the actual delivery of bioactive materialduring introduction and deployment of the device in a patient. Such atest is straightforward and is believed not to entail an undue amount ofexperimentation, particularly in comparison to the amount and technicallevel of testing required before a product of this type can be marketedin the United States.

The medical device of the present invention and its method ofmanufacture have several advantages over prior stents and other medicaldevices and methods for manufacturing them. The time and cost ofmanufacture of the medical device are minimized by the absence of anysteps to incorporate the bioactive material in a containment layer, orto apply a containment or time-release layer over the bioactivematerial. The particularly preferred use of sodium bicarbonate as theabrasive to treat, roughen, or texture the surface of the base materialof the structure enjoys several indirect cost savings resulting from thelow toxicity of the sodium bicarbonate to production workers, the easeof product and waste cleanup, and the biocompatibility of any residualsodium bicarbonate. Worker safety and ease of product and waste cleanupare, of course, important advantages in their own right.

In a first aspect, then, the present invention is directed to a medicaldevice comprising: a structure adapted for introduction into a patient,the structure comprising a base material (preferably non-porous) havinga at least one of a roughened, uneven, unsmooth, or textured surface;and a layer of a bioactive material posited directly upon the surface ofthe base material of the structure. Furthermore, the medical device doesnot require or is free of any additional coating or layer atop the layerof bioactive material for delivering the bioactive material. Thestructure is preferably configured as a stent, such as a vascular orother stent. In another aspect of this invention, the medical device isa delivery device such as an expandable balloon of which a stent ismounted thereon. The balloon material is treated so as to be capable ofdelivering the bioactive material to the treatment site. The balloonmaterial preferably includes a polyamide such as nylon or nylon 12 forapplying the bioactive material directly thereto. As previouslysuggested, a hydrophilic slip coating can be applied to the surface ofthe medical delivery device to further facilitate the delivery andattachment of the lipophilic bioactive material to the vessel wall.Other balloon materials include PEBAX, polyethylene or irradiatedpolyethylene which has a smooth or slippery surface.

The base material of the structure preferably comprises at least one of:stainless steel, tantalum, titanium, nitinol, gold, platinum, inconel,iridium, silver, tungsten, or another biocompatible metal, or alloys ofany of these; carbon or carbon fiber; cellulose acetate, cellulosenitrate, silicone, polyethylene terephthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these.

The bioactive material of the layer on the roughened, uneven, unsmooth,or textured surface of the base material preferably comprises at leastone of: paclitaxel; estrogen or estrogen derivatives; heparin or anotherthrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopidineor another antiplatelet agent; colchicine or another antimitotic, oranother microtubule inhibitor; cytochalasin or another actin inhibitor;a remodelling inhibitor; deoxyribonucleic acid, an antisense nucleotideor another agent for molecular genetic intervention; GP IIb/IIIa, GPIb-IX or another inhibitor or surface glycoprotein receptor;methotrexate or another antimetabolite or antiproliferative agent; ananti-cancer chemotherapeutic agent; dexamethasone, dexamethasone sodiumphosphate, dexamethasone acetate or another dexamethasone derivative, oranother anti-inflammatory steroid; dopamine, bromocriptine mesylate,pergolide mesylate or another dopamine agonist; ⁶⁰Co (having a half lifeof 5.3 years), ¹⁹²Ir (73.8 days), ³²P (14.3 days), ¹¹¹In (68 hours), ⁹⁰Y(64 hours), ⁹⁹mTc (6 hours) or another radiotherapeutic agent;iodine-containing compounds, barium-containing compounds, gold,tantalum, platinum, tungsten or another heavy metal functioning as aradiopaque agent; a peptide, a protein, an enzyme, an extracellularmatrix component, a cellular component or another biologic agent;captopril, enalapril or another angiotensin converting enzyme (ACE)inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase,deferoxyamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxidant; angiopeptin; a ¹⁴C-, ³H-, ¹³¹I,³²P- or ³⁶S-radiolabelled form or other radiolabelled form of any of theforegoing; or a mixture of any of these.

Preferably, the roughened, uneven, unsmooth, or textured surface of thebase material of the structure has a mean surface roughness of about 10μin. (about 250 nm) and a surface roughness range between about 1 μin.and about 100 μin. (about 25 nm and about 2.5 μm).

In a second aspect, the present invention is directed to a medicaldevice comprising: a structure adapted for introduction into a patient,the structure comprising a base material having a roughened, uneven,unsmooth, or textured surface, the structure being configured as avascular stent and the base material comprising at least one ofstainless steel, nitinol, or an allow of nickel and titanium; and alayer of a bioactive material posited directly upon the roughened ortextured surface of the base material of the structure, the bioactivematerial comprising paclitaxel; wherein the medical device does notrequire or is free of any additional coating or layer atop the layer ofbioactive material; and wherein the roughened or textured surface of thebase material of the structure has a mean surface roughness of about 10μin. (about 250 nm) and a surface roughness range between about 1 μin.and about 100 μin. (about 25 nm and about 2.5 μm).

In a third aspect, the present invention is directed to a method ofmanufacturing a medical device comprising the steps of: providing astructure adapted for introduction into a patient, the structurecomprising a base material (preferably non-porous) having a surface;roughening or texturing the surface of the base material of thestructure; and positing a layer of a bioactive material directly uponthe roughened or textured surface of the base material of the structure;the method being characterized in that the resulting medical device doesnot require or is free of any additional coating or layer atop the layerof bioactive material.

Preferably, the method is carried out with a structure configured as astent, such as a vascular stent. The method is preferably carried outwith a base material and a bioactive material as described in the firstaspect of the invention above.

The positing step of the method is preferably carried out by spraying asolution of the bioactive material on the roughened or textured surfaceof the base material of the structure. Dipping the base material in asolution of the bioactive material is also contemplated in the practiceof the present invention.

The roughening or texturing step of the method is preferably carried outby abrading the surface of the base material of the structure. Etchingof the surface is also contemplated in the practice of the presentinvention.

Abrading of the surface of the base material is preferably carried outwith an abrasive grit comprising at least one of sodium bicarbonate(USP), calcium carbonate, aluminum oxide, colmanite (calcium borate),crushed glass or crushed walnut shells. More preferably, the abrading iscarried out with an abrasive grit having a particle size of about 5microns (5 μm) to about 500 microns (500 μm). Even more preferably, theabrading is carried out with sodium bicarbonate (USP) having a nominalparticle size of about 50 microns (50 μm).

Abrading of the surface of the base material is preferably carried outwith an abrasive grit delivered at a pressure under flow of about 5 toabout 200 PSI (about 34 to about 1380 KPa) and at a grit feed rate ofabout 1 to about 1000 g/min. Abrading of the surface is preferablycarried out so as to yield a textured surface on the base materialhaving a mean surface roughness of about 10 μin. (about 250 nm) and asurface roughness range between about 1 μin. and about 100 μin. (about25 nm and about 2.5 μm).

In another aspect, the present invention is directed to the product ofthe method described in the third aspect of the invention, above. In yeta further aspect, the present invention is directed to a method ofmedical treatment or diagnosis which comprises introducing the medicaldevice of the present invention, or the product of the method of thepresent invention, into a human or veterinary patient.

Again, as indicated above, the medical device of the present inventionand its method of manufacture have several advantages over prior stentsand other medical devices and methods for manufacturing them. The timeand cost of manufacture of the medical device of the present inventionare minimized by the absence of any steps to incorporate the bioactivematerial in a containment layer, or to apply a containment ortime-release layer over the bioactive material. The particularlypreferred use of sodium bicarbonate as the abrasive to roughen ortexture the surface of the base material of the structure enjoys costsavings resulting from the low toxicity of the sodium bicarbonate toproduction workers, the ease of product and waste cleanup, and thebiocompatibility of any residual sodium bicarbonate. It should gowithout saying that the good worker safety and ease of product and wastecleanup enjoyed by the method of the present invention are highlydesirable advantages, without regard to any costs saved.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention will now be had uponreference to the following detailed description, when read inconjunction with the accompanying drawing, wherein like referencecharacters refer to like parts throughout the several views, and inwhich:

FIG. 1 is a side view showing one of the steps of the method of thepreferred embodiment of the present invention;

FIG. 2 is an enlarged cross-sectional view of a portion of the medicaldevice and product of the preferred embodiment of the present invention;

FIG. 3 depicts another preferred embodiment of the present invention inwhich a coated medical device such as a coated stent is mounted orpositioned on another medical device such as an inflatable balloon witha bioactive material disposed on at least the outer surface of theballoon;

FIG. 4 depicts an enlarged and longitudinally cross-sectioned view ofthe medical device stent mounted on the medical device balloon of FIG.3;

FIG. 5 depicts a coated medical device stent of the present inventionmounted on medical device balloon which has been positioned in a vesseland expanded therein;

FIG. 6 depicts the coated expanded medical device stent implanted in thevessel of FIG. 5 with the medical device balloon having been deflatedand removed from the treatment site;

FIG. 7 depicts an enlarged cross-section end view of the balloon of FIG.5 in which the folds of the balloon unfurl during expansion and makecontact with the inner surface of a vessel; and

FIGS. 8-11 depict various embodiments of the bioactive material layersof the present invention posited on the base material of a medicaldevice stent and a medical device balloon.

DETAILED DESCRIPTION

With reference now to the Figures, an implantable medical device 10 inaccordance with the present invention is thereshown. The medical device10 of the present invention first comprises a structure 12 adapted fortemporary or permanent introduction into a human or veterinary patient.“Adapted” means that the structure 12 is particularly configured, shapedand sized for such introduction. By way of example, the structure 12 ismost preferably configured as a vascular stent adapted for insertioninto the vascular system of the patient.

The structure 12 can of course be particularly configured for use inother systems and sites such as the esophagus, trachea, colon, biliaryducts, urethra and ureters, among others. Indeed, the structure 12 canalternatively be configured as any conventional vascular or othercomparable medical device, and can include any of a variety ofconventional stent or other adjuncts, such as helically wound strands,perforated cylinders or the like. Moreover, because the problemsaddressed by the present invention arise primarily with respect to thoseportions of the device actually positioned within the patient, theinserted structure 12 need not be an entire device, but can merely bethat portion of a vascular or other device which is intended to beintroduced into the patient. Accordingly, the structure 12 can beconfigured as at least one of, or any portion of, a catheter, a wireguide, a cannula, a stent, a vascular or other graft, a cardiacpacemaker lead or lead tip, a cardiac defibrillator lead or lead tip, aheart valve, a suture, a needle, an angioplasty device or a pacemaker.The structure 12 can also be configured as a combination of portions ofany of these.

For ease of understanding the present invention, FIGS. 1 and 2 show onlya structure 12 configured as a stent, and more particularly, a vascularstent. More preferably, the structure 12 is configured as a vascularstent such as the “LOGIC” stent, the “V-FLEX PLUS” stent, or the“ACHIEVE” stent, all commercially available from Cook Incorporated,Bloomington, Ind. Such stents are cut from a cannula of suitablematerial and possess a plurality of interconnected struts allowing thestents to expand upon inflation of a balloon on which they are carried.They possess a flat outer surface, which as a practical matter makesthem easier to process via the present invention than stents made of aplurality of round wires; the latter are more difficult to abrade. Thesestents possess a smooth inside surface to reduce the possibility ofthrombogenesis.

The particular shape and dimensions of the structure 12 should of coursebe selected as required for its specific purpose and for the particularsite in the patient at which it will be employed, such as in thecoronary arteries, aorta, esophagus, trachea, colon, biliary tract orurinary tract. A structure 12 intended for each location will havedifferent dimensions particularly suited to such use. For example,aortic, esophageal, tracheal and colonic stents may have diameters up toabout 25 mm and lengths about 100 mm or longer. Vascular stents aregenerally shorter, typically about 10 to 60 mm in length, and oftenpreferably about 12 to 25 mm in length. Such vascular stents aretypically designed to expand to a diameter of about 2 to 6 mm wheninserted into the vascular system of a patient, often preferably about 2to 4 mm.

The structure 12 is composed of a base material 14 suitable for theintended use of the structure 12. The base material 14 is preferablybiocompatible. A variety of conventional materials can be employed asthe base material 14. Some materials may be more useful for structuresother than the coronary stent exemplifying the structure 12. The basematerial 14 may be either elastic or inelastic as required for itsintended use in the patient. The base material may be eitherbiodegradable or nonbiodegradable, and a variety of biodegradablepolymers are known. The base material 14 can also be porous orpreferably non-porous, again based on its intended use or application.

Accordingly, the base material 14 can include at least one of stainlesssteel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium,silver, tungsten, or another biocompatible metal, or alloys of any ofthese; carbon or carbon fiber; cellulose acetate, cellulose nitrate,silicone, polyethylene terephthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these. Stainless steel is particularly useful as thebase material 14 when the structure 12 is configured as a vascularstent. In the practice of the present invention, however, particularlypreferred base materials 14 include stainless steel, nitinol, tantalum,polylactic acid, polyglycolic acid and biodegradable materials.Molybdenum-rhenium alloy and magnesium may also possibly be useful basematerials 14 as well.

Of course, when the structure 12 is composed of a radiolucent materialsuch as polypropylene, polyethylene or others above, a conventionalradiopaque marker or coating may and preferably should be applied to itat some limited location. The radiopaque marker or coating provides ameans for identifying the location of the structure 12 by X-ray orfluoroscopy during or after its introduction into the patient's vascularsystem.

The base material 14 of the structure 12 of the medical device 10 of thepresent invention includes a roughened or textured surface 16 extendingat least partly over the base material 14. The surface 16 is roughenedor textured in a manner described in more detail below. While thesurface 16 can be the entire surface of the base material 14, in thepreferred embodiment of the present invention (where the structure 12 isconfigured as a vascular stent) the surface 16 is the outer surface ofthe base material 14.

The medical device 10 of the present invention further comprises atleast one layer 18 of a bioactive material posited directly upon theroughened or textured surface 16 of the base material 14 of thestructure 12. The medical device 10 of the present invention ischaracterized in that it does not require or is free of any additionalcoating or layer atop the layer 18 of bioactive material. Although, itis to be understood that for any reason an additional coating or layeratop or below the layer 18 of bioactive is desired, such coating orlayer can be applied and still be within the contemplation of thepresent invention. The layer 18 may be smoother or rougher than theroughened or textured surface 16.

The base material 14 of the structure 12 is preferably non-porous,although the structure 12 itself can be perforate. The differencebetween a porous material and a non-porous but perforate material is apractical one; the relatively smaller open cells of a porous materialare of a character and number sufficient to retain an appreciable amountof an applied bioactive material therein, while the relatively largerperforations of a non-porous material are of a character and numberwhich are not sufficient to retain an appreciable amount of an appliedbioactive material therein. Alternatively, the open cells of a porousmaterial can be considered generally microscopic, while perforationsthrough a non-porous material can be considered generally macroscopic.

A vast range of drugs, medicants and materials can be employed as thebioactive material in the layer 18. Particularly useful in the practiceof the present invention are materials which prevent or ameliorateabrupt closure and restenosis of blood vessels previously opened bystenting surgery or other procedures. Thrombolytics (which dissolve,break up or disperse thrombi) and antithrombogenics (which interferewith or prevent the formation of thrombi) are especially usefulbioactive materials when the structure 12 is a vascular stent.Particularly preferred thrombolytics are urokinase, streptokinase andthe tissue plasminogen activators. Particularly preferredantithrombogenics are heparin, hirudin and the antiplatelets.

Urokinase is a plasminogen activating enzyme typically obtained fromhuman kidney cell cultures. Urokinase catalyzes the conversion ofplasminogen into the fibrinolytic plasmin, which breaks down fibrinthrombi.

Heparin is a mucopolysaccharide anticoagulant typically obtained fromporcine intestinal mucosa or bovine lung. Heparin acts as a thrombininhibitor by greatly enhancing the effects of the blood's endogenousantithrombin III. Thrombin, a potent enzyme in the coagulation cascade,is key in catalyzing the formation of fibrin. Therefore, by inhibitingthrombin, heparin inhibits the formation of fibrin thrombi.

Of course, bioactive materials having other functions can also besuccessfully delivered by the device 10 of the present invention. Forexample, an antiproliferative agent such as methotrexate will inhibitover-proliferation of smooth muscle cells and thus inhibit restenosis ofthe dilated segment of the blood vessel. Additionally, localizeddelivery of an antiproliferative agent is also useful for the treatmentof a variety of malignant conditions characterized by highly vasculargrowth. In such cases, the device 10 of the present invention could beplaced in the arterial supply of the tumor to provide a means ofdelivering a relatively high dose of the antiproliferative agentdirectly to the tumor.

A vasodilator such as a calcium channel blocker or a nitrate willsuppress vasospasm, which is common following angioplasty procedures.Vasospasm occurs as a response to injury of a blood vessel, and thetendency toward vasospasm decreases as the vessel heals. Accordingly,the vasodilator is desirably supplied over a period of about two tothree weeks. Of course, trauma from angioplasty is not the only vesselinjury which can cause vasospasm, and the device 10 may be introducedinto vessels other than the coronary arteries, such as the aorta,carotid arteries, renal arteries, iliac arteries or peripheral arteriesfor the prevention of vasospasm in them.

A variety of other bioactive materials are particularly suitable for usewhen the structure 12 is configured as something other than a coronarystent. For example, an anti-cancer chemotherapeutic agent can bedelivered by the device 10 to a localized tumor. More particularly, thedevice 10 can be placed in an artery supplying blood to the tumor orelsewhere to deliver a relatively high and prolonged dose of the agentdirectly to the tumor, while limiting systemic exposure and toxicity.The agent may be a curative, a pre-operative debulker reducing the sizeof the tumor, or a palliative which eases the symptoms of the disease.It should be noted that the bioactive material in the present inventionis delivered across the device 10, and not by passage from an outsidesource through any lumen defined in the device 10, such as through acatheter employed for conventional chemotherapy. The bioactive materialof the present invention may, of course, be released from the device 10into any lumen defined in it, and that lumen may carry some other agentto be delivered through it.

Paclitaxel is a particularly preferred anti-cancer agent and/oranti-angiogenic agent as the bioactive material of the layer 18.Paclitaxel is also a lipophilic bioactive material that is attracted bythe lipids in the endothelial and smooth muscle wall cells of thevessel. When applied to the implantable medical device such as a stentof the present invention, the stent maintains the bioactive materiallayer 18 in direct contact with the vessel wall. In another aspect whichwill be hereinafter described, Paclitaxel is applied to a medical devicesuch as a balloon which is used for delivering another medical devicesuch as a stent to a treatment site. The Paclitaxel coating on theballoon material is then brought in direct contact of the vessel wallfor only that period of the inflation of the balloon which is typicallyin the neighborhood of approximately one minute. Theangiogenesis-dependent diseases are those diseases which require orinduce vascular growth, for example, certain types of cancer. Estrogenand estrogen derivatives are also particularly preferred as thebioactive material of the layer 18.

Dopamine or a dopamine agonist such as bromocriptine mesylate orpergolide mesylate is useful for the treatment of neurological disorderssuch as Parkinson's disease. The device 10 could be placed in thevascular supply of the thalamic substantia nigra for this purpose, orelsewhere, localizing treatment in the thalamus.

The present invention also contemplates the use of bioactive materialswhich covalently bond to the roughened or textured surface 16 of thebase material 14 of the structure 12.

It should be clear that a wide range of other bioactive materials can bedelivered by the device 10. Accordingly, it is preferred that thebioactive material of the layer 18 comprises at least one of:paclitaxel; estrogen or estrogen derivatives; heparin or anotherthrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopidineor another antiplatelet agent; colchicine or another antimitotic, oranother microtubule inhibitor; cytochalasin or another actin inhibitor;a remodelling inhibitor; deoxyribonucleic acid, an antisense nucleotideor another agent for molecular genetic intervention; GP IIb/IIIa, GPIb-IX or another inhibitor or surface glycoprotein receptor;methotrexate or another antimetabolite or antiproliferative agent; ananti-cancer chemotherapeutic agent; dexamethasone, dexamethasone sodiumphosphate, dexamethasone acetate or another dexamethasone derivative, oranother anti-inflammatory steroid; an immunosuppressive agent (such ascyclosporin or rapamycin); an antibiotic (such as streptomycin,erythromycin or vancomycin); dopamine, bromocriptine mesylate, pergolidemesylate or another dopamine agonist; ⁶⁰Co (having a half life of 5.3years), ¹⁹²Ir (73.8 days), ³²P (14.3 days), ¹¹¹In (68 hours), ⁹⁰Y (64hours), ⁹⁹mTc (6 hours) or another radiotherapeutic agent;iodine-containing compounds, barium-containing compounds, gold,tantalum, platinum, tungsten or another heavy metal functioning as aradiopaque agent; a peptide, a protein, an enzyme, an extracellularmatrix component, a cellular component or another biologic agent;captopril, enalapril or another angiotensin converting enzyme (ACE)inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase,deferoxyamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxidant; angiopeptin; a ¹⁴C-, ³H-,¹³¹I-, ³²P- or ³⁶S-radiolabelled form or other radiolabelled form of anyof the foregoing; or a mixture of any of these.

When the structure 12 is configured as a vascular stent, however,particularly preferred materials for the bioactive material of the layer18 are heparin, anti-inflammatory steroids including but not limited todexamethasone and its derivatives, and mixtures of heparin and suchsteroids.

Other materials may possibly be useful as the bioactive material in thepractice of the present invention, including: smooth muscle cellinhibitors, collagen inhibitors, anti-coagulants and cholesterolreducing agents; forskolin, vapiprost, prostaglandin and analoguesthereof, prostacyclin and prostacyclin analogues, dextran anddipyridamole; angiotensin converting enzyme inhibitors such asCaptopril® (available from Squibb), Cilazapril® (available fromHoffman-LaRoche), or Lisinopril® (available from Merck); fibroblastgrowth factor (FGF) antagonists, fish oil (omega 3-fatty acid),histamine antagonists, Lovastatin® (an inhibitor of HMG-CoA reductase, acholesterol-lowering drug from Merck), methotrexate, monoclonalantibodies (such as to PDGF receptors), nitroprusside, phosphodiesteraseinhibitors, prostaglandin inhibitor (available from Glaxo), vascularendothelial growth factor (VEGF) or analogues thereof, various cellcycle inhibitors such as the protein product of the retinoblastoma tumorsuppressor gene or analogues thereof), Seramin (a PDGF antagonist),serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide, alpha-interferonand genetically engineered epithelial cells.

The present invention is also directed to a method of manufacturing themedical device 10 disclosed above. More particularly, the method of thepresent invention first comprises providing a structure 12 adapted forthe temporary or permanent introduction into a patient. The structure 12comprises a preferably non-porous base material 14 having a surface 16and is configured, for example, as a stent (such as a vascular stent).The structure 12 and the base material 14 have been described in detailabove, and for brevity, such details will not be repeated here.Stainless steel, nitinol, tantalum, polylactic acid, polyglycolic acidand biodegradable materials are particularly preferred as the basematerial 14 of the structure 12.

The method of the present invention further comprises the steps ofattaining a desired roughness or texture on the surface 16 of the basematerial 14 of the structure 12, and positing a layer 18 of a bioactivematerial directly upon the roughened or textured surface 16 of the basematerial 14. A wide range of bioactive materials useful in the layer 18has been disclosed in detail above; again, for brevity, such detail willnot be repeated. Paclitaxel, a taxane or another paclitaxel analogue,estrogen and estrogen derivatives are particularly preferred asbioactive materials in the layer 18.

The method of manufacturing a medical device 10 according to the presentinvention is characterized in that the resulting medical device 10 doesnot require or is free of any additional coating or layer atop the layer18 of bioactive material. The method of the present invention thereforedoes not include any steps in which the bioactive material is covered byor contained within a time-release or containment layer. While themethod of the present invention contemplates the use of a base material14 which itself comprises a plurality of layers or constituents, such anarrangement may not be preferred in the practice of the presentinvention. In any event, it would be the outermost one of such plurallayers or constituents which possesses the roughened or textured surface16 on which the layer 18 of bioactive material is posited directly.

The step of directly positing the layer 18 of bioactive material on theroughened or textured surface 16 of the base material 14 can be carriedout in any convenient manner. The structure 12 (or suitable portionthereof) can be dipped or soaked in an appropriate solution of thedesired bioactive material, and the solvent of the solution evaporatedto leave a layer 18 of the bioactive material on the roughened ortextured surface 16 of the base material 14. Preferably, however, thepositing step is carried out by spraying a solution of the bioactivematerial on the roughened or textured surface 16 of the base material 14of the structure 12 and allowing the structure 12 to dry. While sprayingmay have a relatively low efficiency in transferring the bioactivematerial to the roughened or textured surface 16, it is adequate for thepurposes of the present invention.

By way of example, paclitaxel (the particularly preferred bioactivematerial in the present invention) can be posited by spraying anethanolic solution of it on the roughened or textured surface 16 of thebase material 14. The solution conveniently contains about 2 to about 4mg of paclitaxel per ml of ethanol. (The ethanol should be 100% USPgrade or equivalent, not denatured alcohol or 95% ethanol.) Taking astent of 15 mm in length and 3 mm in diameter as typical, having atextured, gross outer surface area on the order of 25 mm2, spraying canbe readily carried out to posit about 5 to about 500 μg, preferably 50to 150 μg, of paclitaxel on the roughened or textured surface 16 of thebase material 14. Perhaps less than about 1% of the paclitaxel isultimately posited from solution onto the textured surface 16. Theselection of suitable solvents and concentrations for other bioactivematerials, or the selection of other techniques for positing otherbioactive materials directly upon the roughened or textured surface 16,should be well within the skill of those in the art in view of thepresent disclosure. Any experimentation required should be minimal,particularly in view of the extensive testing required before devices ofthis type can be distributed in the U.S.

The surface 16 of the base material 14 of the structure 12 can beroughened or textured in any convenient manner, such as by etching.Preferably, however, the surface 16 is roughened or textured byabrading, for example, by abrading with an abrasive grit 24 comprisingat least one of sodium bicarbonate (USP), calcium carbonate, aluminumoxide, colmanite (calcium borate), crushed glass, crushed walnut shells,or mixtures of these or other abrasive particulates. Such roughening ortexturing is most easily carried out by placing the medical device 10 ona mandrel 20 in a position such that abrasive grit 24 delivered from anozzle 22 impinges on the surface 16. The initial surface of the basematerial prior to roughening or texturing may be smoother than thedesired surface roughness, or it may be even rougher.

The grit size and feed rate of the abrasive grit 24, the structure ofthe nozzle 22, the pressure at which the abrasive grit 24 is deliveredfrom the nozzle 22, the distance of the surface 16 from the nozzle 22and the rate of relative movement of the medical device 10 and thenozzle 22 are all factors to be considered in achieving an appropriatedesired roughness or texture of the surface 16 of the base material 14of the structure 12. By way of non-limiting example, when the basematerial 14 is stainless steel, the abrading step can be carried outwith an abrasive grit 24 having a particle size of about 5 microns (5μm) to about 500 microns (500 μm). More preferably, the abrading step iscarried out with sodium bicarbonate (USP) having a nominal particle sizeof about 50 microns (50 μm), with approximately 50% greater than 40microns (40 μm) and approximately 1% greater than 150 microns (150 μm).Such abrading is preferably carried out with the sodium bicarbonate orother abrasive grit 24 delivered at a pressure under flow of about 5 toabout 200 PSI (about 34 to about 1380 KPa), most preferably about 100PSI (about 690 KPa). Such abrading is also preferably carried out withthe sodium bicarbonate or other abrasive grit 24 delivered at a gritfeed rate of about 1 to about 1000 g/min, most preferably about 10 toabout 15 g/min.

The carrier gas or propellant for delivery of the abrasive grit ispreferably nitrogen, air or argon, and most preferably nitrogen,although other gases may be suitable as well. When the medical device 10is configured as disclosed above, the distance from the outlet of thenozzle 22 to the center of the mandrel 20 can be about 1 to about 100mm. A preferred nozzle 22 is the Comco Microblaster; when employed, thepreferred distance from the outlet of the nozzle 22 to the center of themandrel 20 is about 5 to about 10 mm. The Paasche LAC #3 is also usefulas the nozzle 22.

To provide a uniform roughening or texturing of the surface 16 of thebase material 14 of the structure 12, it is highly desirable thatrelative movement of the surface 16 and the nozzle 22 be provided duringabrasion of the surface 16. Any pattern of motion which achieves thedesired uniformity of roughness or texture may be employed. It ispreferred that such motion entail both longitudinal or lengthwisemovement along the structure 12 and circumferential movement orrepositioning about the structure 12. Repeated longitudinal movementwith repeated passes at different circumferential positions is mostpreferable. More particularly, abrading of the surface 16 can entailfrom 1 to about 50 axial passes per circumferential position, while thenumber of circumferential positions for such axial passes can range fromabout 4 to an unlimited number of circumferential positions. This lastis achieved by continuous relative rotation of the surface 16 and thenozzle 22. The sweep rate of the nozzle 22 along the surface 16 canrange from about 1 to about 70 mm/sec for the particular stentdimensions disclosed above.

When the base material 14 of the structure 12 is stainless steel, andthe abrasive grit 24 is 50 micron sodium bicarbonate (USP), aparticularly preferred combination of abrading conditions is:

Nozzle 22: Comco Microblaster

Propellant: Nitrogen gas

Pressure: 120 PSI (828 KPa) (under flow)

Spray plan: 8 equally-spaced circumferential positions

4 axial passes per circumferential position

Sweep rate: About 16 mm/sec

Grit feed rate: About 0.15 to 0.30 g/sec

Nozzle outlet to mandrel center: about 5 to 10 mm

When abrading is carried out in this manner, a roughened or texturedsurface 16 is obtained which is thought to have a mean surface roughness(that is, a mean height of surface features) of about 10 μin. (about 250nm) and a surface roughness range between about 1 μin. and about 100μin. (about 25 nm and about 2.5 μm). Such a surface 16 is capable ofretaining on it a highly substantial portion of bioactive materialposited directly on it without requiring any additional covering orcontainment layer.

More particularly, the adhesion of paclitaxel to two types of stainlesssteel, grit abraded stents was compared to its adhesion to stents ofthose types whose surfaces had instead been plasma treated prior to thedirect deposition of paclitaxel thereon (control stents). The coatedstents of both types, that is, medical devices 10 of the presentinvention and control stents, were then subjected to a physical adhesiontest which simulated the rate at which paclitaxel would be deliveredduring introduction and deployment of the stents in clinical use. Theadhesion test involved passing each stent through a water-filled guidingcatheter of appropriate diameter and inflating the balloon catheter toexpand each stent to its intended diameter. The stents are alreadymounted before coating. The amount of paclitaxel remaining on each stentwas then measured by spectrometry and compared to the amount ofpaclitaxel initially posited on each stent. Stents having surfaces 16roughened or textured by abrasion with different abrasive grits 24retained 84.1±10.2% of the paclitaxel originally applied, while stentshaving plasma treated surfaces retained only 44.3±8.7% of the paclitaxeloriginally applied (p<0.0001). This appears to demonstrate thesuccessful retention of the layer 18 of bioactive material on theroughened or textured surface 16 of the base material 14 of thestructure 12 of the medical device 10 of the present invention.

In view of the foregoing disclosure, those skilled in the art shouldreadily be able to perform any trial-and-error testing to obtain theoptimal processing conditions for any desired combination of particularbase materials 14 and bioactive materials. Such testing simply requiresroughening or texturing the surface 16 of a particular base material 14in a selected manner, applying a layer 18 of a particular bioactivematerial to the roughened or textured surface 16 and measuring theretention of bioactive material on the roughened or textured surface 16after clinical introduction and deployment has been mimicked.

It should be clear that the present invention provides a medical device10 and method for manufacturing the same which is particularlyadvantageous over prior devices and methods for making such devices. Thetime and cost of manufacture of the medical device of the presentinvention are minimized by the absence of any steps to incorporate thebioactive material in a containment layer, or to apply a containment ortime-release layer over the bioactive material. The particularlypreferred use of sodium bicarbonate as the abrasive to provide roughnessor texture to the surface of the base material of the structure isadvantageous in the low toxicity of the sodium bicarbonate to productionworkers, the ease of product and waste cleanup, and the biocompatibilityof any residual sodium bicarbonate. These are important advantages intheir own right, but incidentally also reduce the time and cost formanufacture of the medical device 10.

The details of the construction or composition of the various elementsof the medical device 10 of the present invention not otherwisedisclosed are not believed to be critical to the achievement of theadvantages of the present invention, so long as the elements possess thestrength or mechanical properties needed for them to perform asdisclosed. The selection of any such details of construction is believedto be well within the ability of one of even rudimentary skills in thisarea, in view of the present disclosure. For practical reasons, however,most embodiments of the medical device 10 of the present inventionshould probably be considered to be single-use devices, rather thanbeing reusable.

FIG. 3 depicts another preferred embodiment of the present invention inwhich a coated medical device 10 such as a coated stent is mounted orpositioned on another medical device 26 such as an inflatable balloonwith a bioactive material 28 disposed on the outer surface of theballoon. This bioactive material 28 is preferably a lipophilic bioactivematerial such as paclitaxel and other lipophilic materials such asdexamethozone and the like previously described herein. Furthermore,coated implantable medical device 10 includes a bioactive material layerposited thereon as previously described. This bioactive material layercan also be a lipophilic bioactive material such as bioactive material28 applied to balloon medical device 26. As depicted, balloon ends 30and 32 extend longitudinally beyond respective stent ends 34 and 36. Thefolded balloon ends 30 and 32 extend beyond the end of the stent endsand are coated with lipophilic bioactive material for deposition on thevessel wall extending beyond the ends of the delivered stent. Theballoon 26 is preferably of a polyamid material such as nylon 12 whichis available from COOK, Inc., Bloomington, Ind. The balloon 26 isattached to a catheter shaft 38, which includes a guide wire lumen aswell as an inflation lumen for inflating the balloon.

FIG. 4 depicts an enlarged and longitudinally cross-sectioned view of amedical device stent 10 mounted on medical device balloon 26 of FIG. 3.In this preferred embodiment of medical device stent 10 mounted onmedical device balloon 26, the distal and proximal ends 30 and 32 of theballoon are folded and extend radially outward to the outer diameter ofthe compressed stent. During mounting of the stent on the balloon, thefolded ends of the balloon can extend beyond the outer diameter of thestent. In this particular preferred embodiment of the present invention,the bioactive material layers 18 and 28 are of the same lipophilicbioactive material such as paclitaxel, which is applied to the stent andballoon after the stent is mounted on the balloon. Thus, the paclitaxellipophilic bioactive material coating is applied to the outer surface ofthe balloon and stent. This coating process is as previously described.Thus, the paclitaxel bioactive material layer is applied to the vesselwall when the balloon and stent are expanded in the vessel at thetreatment site.

FIG. 5 depicts medical device stent 10 mounted on medical device balloon26 which has been positioned in vessel 40 and expanded therein. Asshown, that portion of vessel 42 is expanded radially outward due to theexpansion of the stent and balloon to alleviate a stenotic ortraumatized condition of the vessel. Portions of proximal and distalballoon ends 30 and 32 come in direct or physical contact with theradially enlarged portions of vessel wall 40. Thus, the lipophilicbioactive material 28 is applied to the enlarged portions of the vesselcoming in contact therewith as well as bioactive material 18 which is onthe outer surface of the medical device stent 10. This advantageouslynot only treats the enlarged vessel wall supported by stent 10, but alsothe lipophilic bioactive material is applied to the vessel extendingbeyond the ends of the stent and thus eliminating the undesirable edgeeffect associated with stent implantation.

FIG. 6 depicts expanded medical device stent 10 implanted in vessel 40of FIG. 5 with medical device balloon 26 having been deflated andremoved from the treatment site. As such, lipophilic bioactive material18 has been applied to the vessel wall along the length of the stent,and bioactive material 28 is likewise applied to the vessel wallextending beyond the ends of the stent where the previously inflatedballoon ends came in contact with the vessel wall. This drug-deliveredzone 44 extending along the length of the vessel in which the balloonand stent have come in contact with the wall and to which the lipophilicbioactive material has been advantageously applied thereto for treatingthe traumatized or stenosed vessel and minimizing, if not eliminating,any adverse reaction due to the implantation of the stent and deliveryballoon.

FIG. 7 depicts an enlarged cross-section end view of balloon 26 of FIG.5 in which folds 46, 48 and 50 unfold or unfurl during expansion andmaking contact with the inner surface of vessel 40. As the balloonexpands during inflation, folds 46, 48 and 50 unfurl, rotate and come ina wiping contact with the inner surface of vessel 40 in a rotationalmovement indicated by arrows 52, 54 and 56. The lipophilic bioactivematerial disposed on the surface thereof comes in contact with the innersurface of the vessel wall and is posited on the vessel surface andattached thereto with the lipophilic attraction of the cells. Thisrotational or wiping action further ensures a complete circumferentialcoating of the inner vessel surface.

Depicted in FIGS. 8-11 are various embodiments of the bioactive materiallayers posited on the base material of medical device stent 10 andmedical device 26. In FIG. 8, a single layer of lipophilic bioactivematerial 28 is posited or applied to balloon base material 26. In thisembodiment, a single lipophilic coating material is applied to thesurface of the balloon for a direct application to a vessel wall, forexample, after the previous introduction of another stent. This ballooncould be used for an angioplasty procedure without the use of a stent.FIG. 11 depicts the same balloon base material layer 26 of which a layerof hydrophilic material is posited or coated thereon. The lipophilicbioactive material layer is sprayed, posited, or disposed on thehydrophilic or slip coating layer 58. The hydrophilic layer permitseasier detachment or delivery of the lipophilic layer 28 when in contactwith the cells of a vessel wall.

FIG. 9 depicts another preferred embodiment of the present invention ofwhich balloon base material 26 has lipophilic bioactive material 28coated thereon in one operation and then medical device 10 such as astent with base material 14 and then lipophilic bioactive material 18 iscrimped or positioned around the balloon.

FIG. 10 depicts the base and lipophilic material layers of the structureof FIG. 9 with an additional layer of bioactive material 28 sprayed,posited, or disposed therein. This configuration presents an alternativeembodiment for delivering greater doses of the lipophilic bioactivematerial to the cells located on the surface of a vessel wall.

INDUSTRIAL APPLICABILITY

The present invention is useful in the performance of various surgicalprocedures and in the manufacture of devices for the performance ofvarious surgical procedures, and therefore finds applicability in humanand veterinary medicine.

It is to be understood, however, that the above-described device ismerely an illustrative embodiment of the principles of this invention,and that other devices and methods for using them may be devised bythose skilled in the art, without departing from the spirit and scope ofthe invention. It is also to be understood that the invention isdirected to embodiments both comprising and consisting of the disclosedparts. In particular, it is contemplated that only part of a medicaldevice 10 according to the present invention need be coated withbioactive material. It is further contemplated that different parts of amedical device 10 could be coated with different bioactive materials.

It is also to be understood that various parts, recesses, portions,sides, segments, channels, and the like of the device can be positedwith the bioactive material either singly or in combination with otherbioactive, coating, or layering materials. This can be done to furthercontrol the release of the bioactive material to the delivery site. Suchconfigurations are contemplated and disclosed in U.S. Pat. Nos.5,380,299; 5,609,629; 5,824,049; 5,873,904; 6,096,070; 6,299,604;6,370,064; 6,530,951; and 6,744,289 and are incorporated by referenceherein.

As previously suggested, the medical device of the present invention canalso include channels, grooves, recesses, indentations, projections,buildups, and the like to increase the surface area of the device towhich the bioactive material can be posited therein.

It is to be understood that paclitaxel is a lipophilic material and israpidly taken up by cells, particularly containing lipids. Once in thecells, it binds to proteins, which helps keep the paclitaxel forsubsequent use. If paclitaxel is kept around for short times, forexample, 20 minutes, it can still have prolonged effects for up to, forexample, 14 days. The discussion of paclitaxel can be found in variousarticles such as “Paclitaxel Inhibits Arterial Smooth Muscle CellProliferation and Migration in Vitro and in Vivo Using Local DrugDelivery,” Circulation, Vol. 96, No. 2, Jul. 15, 1997, pp. 636. Anotherarticle entitled “Drug Therapy,” New England Journal of Medicine, Apr.13, 1995, pp. 1004.

1-21. (canceled)
 22. A balloon catheter medical device that releases adrug by immediate release for the selective therapy of specific diseasedtissue or an organ part to which said drug will bind, comprising such adrug which is lipophilic, water-insoluble and immediately releasable,adhered to a smooth surface of the balloon of said catheter that comesinto contact with the diseased tissue or organ part, which adhered drugwhen pressed against said tissue or organ part at least for a shorttime, is immediately released into said tissue or organ part, whereinthe concentration of said drug on said surface is up to 20 μg/mm². 23.The device according to claim 22, wherein said balloon cathetercomprises a stent.
 24. The device according to claim 23, wherein theballoon further comprising preformed longitudinal folds is coated withthe drug, and the inclination of said folds to refold is not lost afterinflation.
 25. The device according to claim 23, wherein the balloon iscoated with said drug and comprises smooth material to which said drugadheres sufficiently well to resist forces required for folding,essentially without damage.
 26. The device according to claim 23,wherein only an area covered by folds is coated with the drug that wasdried after application.
 27. The device according to claim 22, whereinsaid balloon catheter does not comprise a stent.
 28. The deviceaccording to claim 22, wherein the lipophilic drug is an inhibitor ofcell proliferation or inflammatory processes, or an antioxidant.
 29. Thedevice according to claim 28, wherein the drug used is paclitaxel orother taxane, rapamycin, a sex hormone, a statin, or a prostacyclin. 30.The device according to claim 28, wherein the lipophilic drug is presentas a dry solid on the smooth surface of the balloon.
 31. The deviceaccording to claim 22, wherein the lipophilic drug is embedded in areadily water-soluble matrix substance to achieve good adhesion to thesmooth surface of the balloon and improve absorption by the tissue. 32.The device according to claim 31, wherein said substance is alow-molecular weight hydrophilic substance with a molecular weight <5000D.
 33. A medical device of claim 32 wherein said drug is paclitaxel andsaid device is an angioplasty balloon catheter having a smooth balloonsurface.
 34. The device according to claim 22, wherein the lipophilicdrug is adsorbed to particles of or applied to the smooth surface of theballoon with, a low-molecular weight matrix.
 35. The device according toclaim 22, having a surface additionally coated with a substance thatinfluences the gliding quality of the device or that prevents bloodcoagulation.
 36. A medical device of claim 22 wherein said drug ispaclitaxel and said device is an angioplasty balloon catheter having asmooth balloon surface.
 37. A method for producing the device accordingto claim 22, comprising applying the lipophilic drug in a solutionmedium using an immersion, spreading, or spraying process to the smoothsurface of the balloon to provide a coating and removing excess mediaand substances that adhere loosely to the surface.
 38. The methodaccording to claim 37, wherein the coating process is carried outrepeatedly to achieve a reproducible increase of the drug content usinga same solution medium and/or excipient.
 39. The method according toclaim 38, wherein ethanol is used as the solution medium.
 40. The methodaccording to claim 37, wherein the folded balloon is used as a drugcarrier and is coated prior to or after sterilization with or without acrimped-on stent.
 41. The method according to claim 40, wherein theballoon is coated with the lipophilic drug in unfolded condition andthen is folded.
 42. The method according to claim 37, wherein a stent isattached prior to or after coating of the balloon.
 43. A method oftreating a vascular disease or circulation disturbance comprisingadministering a device of claim 22 to affected tissue.
 44. A method ofopening a passage in the body comprising administering a device of claim22.
 45. A balloon catheter having folds in its balloon, comprising alipophilic, water-insoluble drug which binds to tissue, said drug beingadhered to a smooth balloon surface in a fashion wherein it isimmediately released upon coming into contact with said tissue, whereina balloon area covered with folds is coated with said drug which hasbeen dried after application, and wherein the concentration of said drugon said surface is up to 20 μg/mm².
 46. The balloon catheter accordingto claim 45, further comprising a stent, a needle or a guiding wire. 47.The balloon catheter according to claim 45, comprising a balloon that,in its finally folded state, is coated with a low-viscosity active agentsolution of said drug, by immersing or spraying.
 48. The ballooncatheter according to claim 45, wherein the lipophilic drug is aninhibitor of cell proliferation or an inflammatory process, or anantioxidant.
 49. The balloon catheter according to claim 48, wherein thedrug is paclitaxel or other taxane, rapamycin, a sex hormone, a statin,or a prostacyclin.
 50. The balloon catheter according to claim 48,wherein the lipophilic drug is present as a dry solid on the surface ofthe balloon.
 51. The balloon catheter according to claim 45, whereinsaid lipophilic drug is embedded in a readily water-soluble matrixsubstance to achieve good adhesion to the surface of the balloon andimproved absorption by the tissue.
 52. The balloon catheter according toclaim 51, wherein said substance is a low-molecular weight hydrophilicsubstance with a molecular weight <5000 D.
 53. A balloon catheter ofclaim 52 wherein said drug is paclitaxel and said device is anangioplasty balloon catheter having a smooth balloon surface.
 54. Theballoon catheter according to claim 51, wherein said substance is acontrast agent.
 55. The balloon catheter according to claim 54, whereinsaid substance is an iodinated X-ray contrast agent.
 56. The ballooncatheter according to claim 45, wherein said lipophilic drug is adsorbedto a particle or applied to the smooth surface of the balloon with alow-molecular weight substance.
 57. The balloon catheter according toclaim 45, having a surface additionally coated with a substance thatinfluences the glidability of the device or that prevents bloodcoagulation.
 58. A balloon catheter of claim 45 wherein said drug ispaclitaxel and said device is an angioplasty balloon catheter having asmooth balloon surface.
 59. A method for producing a balloon catheteraccording to claim 45, comprising applying the lipophilic drug in asolution medium using an immersion, spreading, or spraying process tothe surface of the folded balloon, and removing excess media andsubstances that adhere loosely to the surface.
 60. The method accordingto claim 59, wherein the application process is carried out repeatedlyto achieve a reproducible increase of the drug content using a samesolution medium and/or excipient.
 61. The method according to claim 60,wherein ethanol is used as the solution medium.
 62. The method accordingto claim 59, wherein a folded and substantially ready for use balloon isused as a drug carrier coated before or after sterilization with orwithout a crimped-on stent.
 63. The method according to claim 59,wherein a stent is connected to the balloon catheter before or aftercoating.
 64. A method for the treatment of a vascular disease or adysfunction of circulation comprising administering a catheter of claim45.
 65. A method for opening a passage in the body comprisingadministering a catheter of claim
 45. 66. A method for tumor treatmentcomprising administering a catheter of claim
 45. 67. A balloon cathetermedical device that releases a drug by immediate release for theselective therapy of specific diseased tissue or an organ part to whichsaid drug will bind, comprising such a drug which is lipophilic,water-insoluble and immediately releasable, adhered to a surface of theballoon of said catheter that comes into contact with the diseasedtissue or organ part, which adhered drug when pressed against saidtissue or organ part at least for a short time, is immediately releasedinto said tissue or organ part, wherein the drug is adhered to saidsurface in a manner resulting in an amount of drug retained on saiddevice of about 10% or less after a time period in which said balloonsurface is in contact with said tissue of up to a few minutes, andwherein the concentration of said drug on said surface is up to 20μg/mm².
 68. A balloon catheter of claim 67 wherein said drug ispaclitaxel and said device is an angioplasty balloon catheter having asmooth balloon surface.
 69. The device of claim 22 wherein thelipophilic drug is present as a dry solid on the surface of the device.70. The device of claim 69 wherein the lipophilic drug is paclitaxel.71. The device of claim 69 wherein the dried solid also comprises acontrast agent.
 72. The catheter of claim 45 wherein the lipophilic drugis present as a dry solid on the surface of the device.
 73. The catheterof claim 72 wherein the lipophilic drug is paclitaxel.
 74. The catheterof claim 72 wherein the dried solid also comprises a contrast agent. 75.The device according to claim 22, wherein the concentration of said drugon said surface is up to 5 μg/mm².
 76. The device according to claim 22,wherein the concentration of said drug on said surface is between 0.2and 20 μg/mm².
 77. The device according to claim 45, wherein theconcentration of said drug on said surface is up to 5 μg/mm².
 78. Thedevice according to claim 45, wherein the concentration of said drug onsaid surface is between 0.2 and 20 μg/mm².
 79. The device according toclaim 67, wherein the concentration of said drug on said surface is upto 5 μg/mm².
 80. The device according to claim 67, wherein theconcentration of said drug on said surface is between 0.2 and 20 μg/mm².